Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Nuclear envelope rupture in cardiomyocytes orchestrates early transcriptomic changes and immune activation in LMNA-related dilated cardiomyopathy that are reversed by LINC complex disruption [RNA-seq]

ABSTRACT: Mutations in the LMNA gene, which encodes the nuclear envelope (NE) proteins lamins A and C, cause dilated cardiomyopathy (LMNA-DCM) and other diseases. The pathogenic mechanisms for LMNA-DCM remain poorly understood, limiting current treatment options and leading to high mortality amongst patients. We developed a mouse model with inducible, cardiomyocyte-specific Lmna deletion (cKO) and performed comprehensive bulk, single-nucleus, and spatial transcriptomic analyses across disease progression. Our analysis identified key disease-driving genes involved in cellular responses to DNA damage, cytosolic pattern recognition receptor signaling, and innate immunity that originated from two disease-specific cardiomyocyte subpopulations. Spatial mapping revealed aberrant interactions between these cardiomyocytes, fibroblasts, and immune cells, contributing to tissue-wide transcriptional changes in cKO hearts. Concurrent cardiomyocyte-specific disruption of the LINC complex, which transmits cytoskeletal forces to the nucleus, substantially reduced NE rupture in cKO cardiomyocytes, normalized expression of more than half of the dysregulated genes, and dramatically improved cardiac function and survival in cKO mice. These findings suggest that NE rupture in cKO cardiomyocytes triggers cytosolic DNA sensing pathways and maladaptive cell-cell communication with fibroblasts and immune cells, leading to fibrosis and inflammation driving LMNA-DCM pathogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE304346 | GEO | 2026/09/24

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Nuclear envelope rupture in cardiomyocytes orchestrates early transcriptomic changes and immune activation in LMNA-related dilated cardiomyopathy that are reversed by LINC complex disruption [RNA-seq]

Project description:Mutations in the LMNA gene, which encodes the nuclear envelope (NE) proteins lamins A and C, cause dilated cardiomyopathy (LMNA-DCM) and other diseases. The pathogenic mechanisms for LMNA-DCM remain poorly understood, limiting current treatment options and leading to high mortality amongst patients. We developed a mouse model with inducible, cardiomyocyte-specific Lmna deletion (cKO) and performed comprehensive bulk, single-nucleus, and spatial transcriptomic analyses across disease progression. Our analysis identified key disease-driving genes involved in cellular responses to DNA damage, cytosolic pattern recognition receptor signaling, and innate immunity that originated from two disease-specific cardiomyocyte subpopulations. Spatial mapping revealed aberrant interactions between these cardiomyocytes, fibroblasts, and immune cells, contributing to tissue-wide transcriptional changes in cKO hearts. Concurrent cardiomyocyte-specific disruption of the LINC complex, which transmits cytoskeletal forces to the nucleus, substantially reduced NE rupture in cKO cardiomyocytes, normalized expression of more than half of the dysregulated genes, and dramatically improved cardiac function and survival in cKO mice. These findings suggest that NE rupture in cKO cardiomyocytes triggers cytosolic DNA sensing pathways and maladaptive cell-cell communication with fibroblasts and immune cells, leading to fibrosis and inflammation driving LMNA-DCM pathogenesis.

2026-09-24 | GSE269451 | GEO

2026-09-24 | GSE269452 | GEO

Nuclear envelope rupture in cardiomyocytes orchestrates early transcriptomic changes and immune activation in LMNA-DCM that are reversed by LINC complex disruption

Project description:Mutations in the LMNA gene, which encodes the nuclear envelope (NE) proteins lamins A/C, cause dilated cardiomyopathy (LMNA-DCM) and other diseases. The pathogenic mechanisms for LMNA-DCM remain poorly understood, limiting current treatment options and leading to high mortality amongst patients. We developed a mouse model with inducible, cardiomyocyte-specific Lmna deletion and performed comprehensive transcriptomic analyses (bulk, single-nucleus, and spatial) across disease progression. We identified key disease-driving genes involved in cellular responses to DNA damage, cytosolic pattern recognition receptor signaling, and innate immunity that originated from two disease-specific cardiomyocyte subpopulations. Spatial mapping revealed aberrant interactions between these cardiomyocytes, fibroblasts, and immune cells, contributing to tissue-wide transcriptional changes. Using mice with inducible, cardiomyocyte-specific disruption of the LINC complex, which transmits cytoskeletal forces to the nucleus, we demonstrated that reducing NE rupture corrected ~50% of misregulated genes and dramatically improved cardiac function and survival in the LMNA-DCM mouse model. These findings suggest that loss of nuclear integrity in Lmna-depleted cardiomyocytes triggers cytosolic DNA sensing and maladaptive cell-cell communication with fibroblasts and immune cells, promoting fibrosis and inflammation characteristic of LMNA-DCM.

2026-09-08 | GSE307910 | GEO

Nuclear envelope rupture causes RNA polymerase loss in LMNA cardiomyopathy

Project description:Localized rupture of the nuclear envelope has been reported in various pathologies, including cancer, neurodegenerative disease, myocardial infarction, as well as dilated cardiomyopathy caused by Lamin A/C gene mutations (LMNA-DCM). Whether and how nuclear rupture contributes to disease remains unclear. Here, we report that nuclear rupture causes global transcriptional deficiency in a mouse model of LMNA-DCM. We observed that ruptured nuclei lost chromatin-bound RNA polymerase II, leading to downregulation of numerous genes essential for cardiomyocyte structure and function. Notably, over one third of ruptured nuclei resealed and regained transcription. Resealing involved the ESCRT-III membrane remodeling complex and was cardioprotective, as its blockade increased rupture frequency and accelerated cardiomyopathy. However, resealing was ineffective: resealed nuclei re-ruptured at twice the resealing rate and ten-fold faster than the de novo rupture rate. A mathematical model predicted a steady accumulation of ruptured nuclei despite ongoing resealing. Consistently, a human LMNA-mutant heart contained numerous ruptured nuclei at the time of disease presentation. These findings link nuclear rupture to organ deterioration through global transcriptional deficiency and suggested rupture repair as a critical modifier of nuclear rupture-associated conditions.

2026-04-03 | GSE325163 | GEO

Simtuzumab Attenuates Loxl2-Mediated Extracellular Matrix Remodeling and Preserves Cardiac Function in LMNA Mutation-Induced Dilated Cardiomyopathy

Project description:Background | Dilated cardiomyopathy (DCM) caused by LMNA mutations is a severe cardiac condition marked by arrhythmias, contractile dysfunction, and excessive myocardial fibrosis, which collectively impair left ventricular function and increase the risk of heart failure. While the disease has been well characterized, a lack of insight into the pathogenesis has impeded the development of therapies. Methods | Here, we employed induced pluripotent stem cells (hiPSCs) derived from a patient carrying a LMNA point mutation (c.665A>C, p.His222Pro), alongside a murine model carrying the same mutation, to investigate the functional and molecular abnormalities driving DCM. Results | We demonstrated that LMNA patient-derived cardiomyocytes (hiPSC-CMs) and engineered heart tissues (hiPSC-EHTs) exhibited elevated diastolic calcium levels and reduced sensitivity to external calcium, respectively, as well as hypocontractility. These cells also displayed nuclear shape abnormalities in 2D and 3D, a hallmark of LMNA-associated DCM, associated with disrupted chromosome spatial organization and altered gene expression profiles. Transcriptomic analysis revealed dysregulation of extracellular matrix remodeling and significant upregulation of Loxl2 in mutated hiPSC-CMs, hiPSC-EHTs, and mice. Treatment with Simtuzumab, a Loxl2 inhibitor, effectively prevented cardiac dysfunction and fibrosis in vivo. Conclusion | Taken together, our findings underscore the crucial role of Loxl2 as a therapeutic target and suggest that its inhibition could be a promising strategy to preserve cardiac function in LMNA-associated DCM.

2026-01-30 | GSE312730 | GEO

TEAD1 trapping by the Q353R-Lamin A/C causes dilated cardiomyopathy.

Project description:• Mutations in the LMNA gene encoding Lamin A and C (Lamin A/C), major components of the nuclear lamina, cause laminopathies including dilated cardiomyopathy (DCM), but the underlying molecular mechanisms have not been fully elucidated. Here, by leveraging single-cell RNA-seq, ATAC-seq, protein array, and electron microscopy analysis, we show that insufficient structural maturation of cardiomyocytes owing to trapping of transcription factor TEAD1 by mutant Lamin A/C at the nuclear membrane underlies the pathogenesis of Q353R- LMNA-related DCM. Inhibition of the Hippo pathway rescued the dysregulation of cardiac developmental genes by TEAD1 in LMNA-mutant cardiomyocytes. Single-cell RNA-seq of cardiac tissues from DCM patients with the LMNA mutation confirmed the dysregulated expression of TEAD1 target genes. Our results propose an intervention for transcriptional dysregulation as a potential treatment of LMNA-related DCM.

2023-03-06 | GSE190977 | GEO

Cardiomyocyte-specific lamin A re-expression via AAV-Lmna/DJ8 ameliorates cardiac dysfunction in Lmna⁻/⁻ mice

Project description:Mutations in LMNA, which encodes the nuclear envelope protein lamin A/C, cause laminopathies that frequently present as dilated cardiomyopathy (DCM). We investigated whether re-expression of lamin A in cardiomyocytes can rescue the severe phenotype of Lmna⁻/⁻ mice. An adeno-associated virus vector expressing wild-type Lmna (AAV-Lmna/DJ8) was administered intrathoracically to neonatal mice. Three weeks after injection, treated Lmna⁻/⁻ mice exhibited robust cardiac Lmna mRNA induction and nuclear localization of lamin A protein, reflecting efficient cardiotropic gene delivery. Compared with PBS treatment, AAV-Lmna/DJ8 treatment promoted body weight maintenance, improved left ventricular systolic function, and significantly prolonged survival in Lmna⁻/⁻ mice. To explore the underlying mechanisms, we performed single-nucleus RNA sequencing of cardiomyocytes from wild-type mice, PBS-treated Lmna⁻/⁻ mice, and AAV-Lmna/DJ8–treated Lmna⁻/⁻ mice. AAV-mediated lamin A re-expression shifted the cardiomyocyte transcriptome toward the wild-type profile, and restored oxidative phosphorylation–related gene programs, which were diminished in untreated Lmna⁻/⁻ mice. These findings demonstrate that targeted re-expression of Lmna ameliorates cardiac dysfunction in Lmna⁻/⁻ mice and highlight the therapeutic potential of LMNA gene replacement for laminopathy-associated cardiomyopathy.

2026-05-12 | GSE319519 | GEO

Project description:LMNA-Related DCM involves cardiomyocyte dysfunction resulting in heart failure or sudden death. It is caused by LMNA mutations encoding Lamin A/C defects involved in nuclear integrity and gene expression. To investigate possible mechanisms, we used iPSC derived from a LMNA c.357-2A>G Patient and her unaffected sister. We differentiated iPSC and conducted scRNA-seq for 4 Patient and 8 Control samples across seven time points from Day 0 to 30. Using a comprehensive bioinformatics workflow, we identified 110,521 high-quality cells and complex heterogeneity: ten main cell types, possible subtypes, and lineage bifurcation for Cardiac Progenitors to Cardiomyocytes and Epicardium-Derived Cells (EPDC). By comparative analyses, we found differentially expressed genes (DEG) and enrichment supporting pathway dysregulation for ZNF genes and RNA polymerase II transcription in Pluripotent cells; BMP4 and TGF Beta/BMP signaling, sarcomere genes and cardiogenesis, CDH2 and EMT in Cardiomyocytes; LMNA and epigenetic regulation and DDIT4 and mTORC1 signaling in EPDC. In addition, top DEG included XIST, six imprinted genes, and gene sets in metabolism, proliferation, and homeostasis. We confirmed Lamin A/C haploinsufficiency by allelic expression and Western blot. Our evidence supports disruption of epigenomic developmental programs in LMNA-Related DCM and also demonstrates current challenges of LMNA disease modeling using Patient-derived iPSC.

2024-09-03 | GSE269705 | GEO

Impaired vitamin D signaling causes LMNA mutation-related cardiomyopathy

Project description:Mutations of the lamin A/C gene (LMNA) cause a variety of diseases including dilated cardiomyopathy (DCM). LMNA-related DCM often leads to severe heart failure, but the underlying pathophysiology is unknown. Here we show that vitamin D receptor (VDR) signaling is critically involved in LMNA-related DCM. We established iPS cells from DCM patients with an LMNA mutation and found that the iPS cell-derived cardiomyocytes (iPSCMs) showed remarkable DNA damage and reduced contractility compared with the isogenic control. Screening of a chemical library revealed that vitamin D2 reduced DNA damage of the mutant iPSCMs. RNA sequencing analysis showed that expression levels of putative downstream genes of VDR including DNA repair factors were downregulated in the mutant iPSCMs, which were upregulated by vitamin D2. Protein-protein interaction screening revealed that the binding of VDR to mutant LMNA was more robust than to wild-type LMNA, resulting in attenuated VDR signaling in the mutant iPSCMs. Vitamin D2 administration reduced DNA damage and improved cardiac function in pressure overload-induced heart failure mice. These results indicate that impaired DNA repair caused by reduced transcriptional activity of VDR induces cardiac dysfunction of LMNA-related DCM and suggest that VDR signaling is a potential therapeutic target for patients with DCM and heart failure.

2025-03-01 | GSE182219 | GEO

Pervasive nuclear envelope ruptures precede ECM signaling and disease onset without activating cGAS-STING in Lamin cardiomyopathy mice [SLAM-IT-seq]

Project description:Nuclear envelope (NE) ruptures are emerging observations in Lamin-related dilated cardiomyopathy, an adult-onset disease caused by loss-of-function mutations in Lamin A/C, a nuclear lamina component. Here, we test a prevailing hypothesis that NE ruptures trigger the pathological cGAS-STING cytosolic DNA-sensing pathway using a mouse model of Lamin cardiomyopathy. The reduction of Lamin A/C in cardiomyocytes of adult mice causes pervasive NE ruptures in cardiomyocytes, preceding inflammatory transcription, fibrosis, and fatal dilated cardiomyopathy. NE ruptures are followed by DNA damage accumulation without causing immediate cardiomyocyte death. However, cGAS-STING-dependent inflammatory signaling remains inactive. Deleting cGas or Sting does not rescue cardiomyopathy. The lack of cGAS-STING activation is likely due to the near absence of cGAS expression in adult cardiomyocytes at baseline. Instead, extracellular matrix (ECM) signaling is activated and predicted to initiate pro-inflammatory communication from Lamin-reduced cardiomyocytes to fibroblasts. Our work nominates ECM signaling, not cGAS-STING, as a potential inflammatory contributor in Lamin cardiomyopathy.

2024-04-26 | GSE241589 | GEO